Homochiral syntheses of conformationally locked nucleosides were developed from chiral carbocyclic precursors. The bicyclo[3.1.0]hexane template allowed syntheses of conformationally rigid nucleoside analogues in the Northern hemisphere when the cyclopropane ring was fused between carbons 4' and 6' of the cyclopentane ring, while a locked Southern hemisphere conformation was realized when the fusion of the cyclopropane occurred between carbons 1' and 6'. AZT analogues in both locked conformations failed to have detectable anti-HIV activity. However, the thymidine and adenosine analogues were endowed with potent and selective antiviral activity against the herpes family, including human cytomegalovirus. When incorporated into oligodeoxynucleotides designed as antisense agents, the conformationally locked nucleosides with Northern conformations facilitated the formation of the heteroduplexes with the complementary RNA producing significant increases in the melting temperatures (Tm). The incorporation of both types of conformationally locked nucleosides into the same oligodeoxynucleotides is anticipated to produce short oligomers with a bend similar to that induced on DNA by transcription and integration factors. The expected inhibition of these specific transcription and integration factors resulting from the use of bent oligodeoxynucleotides will be exploited as a possible chemotherapeutic approach to cancer and AIDS.